OBJECTIVEIncreased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.RESEARCH DESIGN AND METHODSLipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor–deficient mice (Ldlr−/−) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.RESULTSIn HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal–related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr−/− mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator–activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.CONCLUSIONSNobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.

These recent studies suggest an important role of citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity and atherosclerosis. The favorable outcomes are achieved through multiple mechanisms. Human studies focussed on dose, bioavailability, efficacy and safety are required to propel the use of these promising therapeutic agents into the clinical arena.

Objective-Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100 -containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis. Methods and Results-Three groups (chow, Western, and Western plus naringenin) were fed ad libitum for 6 months. TheWestern diet increased fasting plasma triglyceride (TG) (5-fold) and cholesterol (8-fold) levels compared with chow, whereas the addition of naringenin significantly decreased both lipids by 50%. The Western-fed mice developed extensive atherosclerosis in the aortic sinus because plaque area was increased by 10-fold compared with chow-fed animals. Quantitation of fat-soluble dye (Sudan IV)-stained aortas, prepared en face, revealed that Western-fed mice also had a 10-fold increase in plaque deposits throughout the arch and in the abdominal sections of the aorta, compared with chow. Atherosclerosis in both areas was significantly decreased by more than 70% in naringenin-treated mice. Consistent with quantitation of aortic lesions, the Western-fed mice had a significant 6-fold increase in cholesterol and a 4-fold increase in TG deposition in the aorta compared with chow-fed mice. Both were reduced more than 50% by naringenin. The Western diet induced extensive hepatic steatosis, with a 10-fold increase in both TG and cholesteryl ester mass compared with chow. The addition of naringenin decreased both liver TG and cholesteryl ester mass by 80%. The hyperinsulinemia and obesity that developed in Western-fed mice was normalized by naringenin to levels observed in chow-fed mice. Conclusion-These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance. Key Words: atherosclerosis Ⅲ naringenin Ⅲ hyperlipidemia Ⅲ insulin resistance Ⅲ obesity A therosclerotic lesions contribute to myocardial infarction and stroke and are responsible for cardiovascular disease developing into a principal cause of death in industrial societies. 1 Major risk factors for atherosclerosis include age, hypertension, diabetes mellitus, smoking, and dyslipidemia. Atherogenic dyslipidemia is characterized by increased plasma concentrations of triglyceride (TG)-rich very low-density lipoprotein (VLDL) and cholesterol-rich LDL and low levels of high-density lipoprotein. Plasma concentrations of apolipoprotein B100 (apoB100)-containing particles directly correlate with plasma cholesterol levels, making a reduction in apoB100 secretion an attractive therapeutic target.The accumulation of cholesteryl ester (CE) within the arterial intima...

Metabolic syndrome is a collection of abnormalities, including obesity, dyslipidemia, hypertension, and insulin resistance, all of which contribute to the development of type 2 diabetes and atherosclerosis. Insulin resistance, dyslipidemia, and atherosclerosis are amplifi ed by the development of a chronic low-grade infl ammatory response ( 1 ). In insulin-resistant states, monocyte-derived macrophages infi ltrate visceral adipose tissue, resulting in proinfl ammatory cytokine synthesis, either from adipocytes or resident macrophages, which impairs insulin sensitivity ( 2, 3 ). Administration of diets rich in saturated fats to Ldlr Ϫ / Ϫ mice represents a model with many characteristics of the metabolic syndrome ( 4-6 ). Recent studies in this Abstract Obesity-associated chronic infl ammation contributes to metabolic dysfunction and propagates atherosclerosis. Recent evidence suggests that increased dietary cholesterol exacerbates infl ammation in adipose tissue and liver, contributing to the proatherogenic milieu. The ability of the citrus fl avonoid naringenin to prevent these cholesterol-induced perturbations is unknown. To assess the ability of naringenin to prevent the amplifi ed infl ammatory response and atherosclerosis induced by dietary cholesterol, male Ldlr ؊ / ؊ mice were fed either a cholesterol-enriched high-fat or low-fat diet supplemented with 3% naringenin for 12 weeks. Naringenin, through induction of hepatic fatty acid (FA) oxidation and attenuation of FA synthesis, prevented hepatic steatosis, hepatic VLDL overproduction, and hyperlipidemia induced by both cholesterol-rich diets. Naringenin attenuated hepatic macrophage infi ltration and infl ammation stimulated by dietary cholesterol. Insulin resistance, adipose tissue expansion, and infl ammation were alleviated by naringenin. Naringenin attenuated the cholesterol-induced formation of both foam cells and expression of infl ammatory markers in peritoneal macrophages. Naringenin signifi cantly decreased atherosclerosis and inhibited the formation of complex lesions, which was associated with normalized aortic lipids and a reversal of aortic infl ammation. We demonstrate that in mice fed cholesterolenriched diets, naringenin attenuates peripheral and systemic infl ammation, leading to protection from atherosclerosis. These studies offer a therapeutically relevant alternative for the prevention of cholesterol-induced metabolic dysregulation. -Assini, J. M., E. E. Mulvihill, B. G. Sutherland, D. E. Telford, C. G. Sawyez, S. L. Felder, S. Chhoker, J. Y. Edwards, R. Gros, and M. W. Huff. Naringenin prevents cholesterol-induced systemic infl ammation, This work was supported by Heart and Stroke Foundation of Ontario (HSFO)Grants , Canadian Foundation for Innovation and Ontario Research Fund (to R.G.), a HSFO Masters Award (to J.M.A.), and a Canadian Institutes of Health Research-Canada Graduate Scholarship Doctoral Award (to E.E.M.). 14 December 2012. Published, JLR Papers in Press, December 19, 2012 DOI 10.1194 Abbreviations: ABCG, ATP-binding...

The molecular mechanisms and metabolic pathways whereby the citrus flavonoid, naringenin, reduces dyslipidemia and improves glucose tolerance were investigated in C57BL6/J wild-type mice and fibroblast growth factor 21 (FGF21) null (Fgf21(-/-)) mice. FGF21 regulates energy homeostasis and the metabolic adaptation to fasting. One avenue of this regulation is through induction of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc1a), a regulator of hepatic fatty acid oxidation and ketogenesis. Because naringenin is a potent activator of hepatic FA oxidation, we hypothesized that induction of FGF21 might be an integral part of naringenin's mechanism of action. Furthermore, we predicted that FGF21 deficiency would potentiate high-fat diet (HFD)-induced metabolic dysregulation and compromise metabolic protection by naringenin. The absence of FGF21 exacerbated the response to a HFD. Interestingly, naringenin supplementation to the HFD robustly prevented obesity in both genotypes. Gene expression analysis suggested that naringenin was not primarily targeting fatty acid metabolism in white adipose tissue. Naringenin corrected hepatic triglyceride concentrations and normalized hepatic expression of Pgc1a, Cpt1a, and Srebf1c in both wild-type and Fgf21(-/-) mice. HFD-fed Fgf21(-/-) mice displayed greater muscle triglyceride deposition, hyperinsulinemia, and impaired glucose tolerance as compared with wild-type mice, confirming the role of FGF21 in insulin sensitivity; however, naringenin supplementation improved these metabolic parameters in both genotypes. We conclude that FGF21 deficiency exacerbates HFD-induced obesity, hepatic steatosis, and insulin resistance. Furthermore, FGF21 is not required for naringenin to protect mice from HFD-induced metabolic dysregulation. Collectively these studies support the concept that naringenin has potent lipid-lowering effects and may act as an insulin sensitizer in vivo.

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